Carla Bizzarri

No protective effect of calcitriol on β-cell function in recent-onset type 1 diabetes the IMDIAB XIII trial.

OBJECTIVE We investigated whether supplementation of the active form of vitamin D (calcitriol) in recent-onset type 1 diabetes can protect β-cell function evaluated by C-peptide and improve glycemic control assessed by A1C and insulin requirement. RESEARCH DESIGN AND METHODS Thirty-four subjects (aged 11–35 years, median 18 years) with recent-onset type 1 diabetes and high basal C-peptide >0.25 nmol/l were randomized in a double-blind trial to 0.25 μg/day calcitriol or placebo and followed-up for 2 years. RESULTS At 6, 12, and 24 months follow-up, A1C and insulin requirement in the calcitriol group did not differ from the placebo group. C-peptide dropped significantly (P < 0.001) but similarly in both groups, with no significant differences at each time point. CONCLUSIONS At the doses used, calcitriol is ineffective in protecting β-cell function in subjects (including children) with recent-onset type 1 diabetes and high C-peptide at diagnosis.

Clinical effects of early treatment with insulin glargine in patients with cystic fibrosis and impaired glucose tolerance

Diabetes mellitus is an increasing complication of cystic fibrosis (CF), as a result of the improved life expectancy. There is clear association between diabetes and increased morbidity and mortality. Lung function and clinical status deteriorate up to 2–4 yr before the diagnosis of cystic fibrosis-related diabetes (CFRD). The aim of our study was to evaluate the effects, on glucose homeostasis and clinical status, of the early treatment with insulin glargine in CF patients with impaired glucose tolerance (IGT). We selected six subjects with IGT diagnosed at oral glucose tolerance test (OGTT). Median age was 18.12 yr (range 9.2–27.8). Insulin glargine was administered at the median dosage of 0.3 U/kg/day (range 0.2–0.5). After the initial adjustment of the dosage, no patient manifested hypoglycemia during treatment. Median glycosylated hemoglobin (HbAIc) did not show any significant variation during treatment: it was 5.9% at baseline (range 5.5–6.2) and 6.1% (range 5.0–6.7) at the end of follow-up (p = 0.496). Median body mass index (BMI) z-score significantly increased during treatment, from −0.95 (range −3.2–+0.6) at baseline to −0.5. (range −3.0–+0.9) at the end of follow-up (p = 0.026). Lung function, measured by median forced expiratory volume in the first second (FEV1%), showed a mild but significant improvement during insulin treatment. It was 72.7% at baseline (range 41.5–98.4) and 76.7% (range 42.0–106.8) at the end of follow-up (p = 0.027). No significant variation was found between the number of hospitalizations for clinical exacerbation (no./patient/yr) in the last 2 yr before treatment and during follow-up. Median number at baseline was 1.95/patient/yr (range 1–3) and 2.0/patient/yr (range 1–3) at follow-up (p = 0.715). Our data seem to indicate that early insulin therapy can be safe, no patient manifested hypoglycemia or other adverse effects during treatment. Insulin is an anabolic hormone implicated in both lipid and protein metabolism. The appearance of IGT out of infections can indicate an early insulin deficiency, with a potential impact on the nutritional and clinical status of the patient, even before the appearance of overt diabetes. Larger controlled trials are necessary to verify if early insulin therapy is able to reduce the deterioration of nutritional status and lung function associated with the onset of IGT. (J. Endocrinol. Invest. 29: RC1-RC4, 2006)

Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene

To the Editor, Activating missense mutations in the gene encoding potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) represent the most common cause (40 to 64%, depending on populations) of permanent neonatal diabetes mellitus in patients diagnosed in the first 6 months of life [1, 2]. In addition, KCNJ11 activating mutations can lead to transient/relapsing neonatal diabetes [3, 4]. The KCNJ11 gene encodes the pore-forming subunit (also known as KIR6.2) of the pancreatic beta cell ATP-sensitive potassium channel (KATP), which exerts a pivotal role in glucose-regulated insulin release. In the beta cell, KIR6.2 forms a hetero-octameric complex (4:4) with the sulfonylurea receptor subtype 1 (SUR1); binding to SUR1 by sulfonylureas determines channel closure and insulin secretion [2]. In previously published cases, seven patients have been reported to respond well to the transfer from insulin to oral hypoglycaemic agents [4–8]. Here we report on the replacement of insulin with sulfonylureas in ten Italian children who have mutations in KCNJ11 (R50P, V59M [x4], K170R, R201C and R201H [x3]) and were followed in nine Diabetologia (2006) 49:2210–2213 DOI 10.1007/s00125-006-0329-x

Abnormal glucose tolerance in children with cystic fibrosis: the predictive role of continuous glucose monitoring system.

UNLABELLED A long pre-diabetic phase of abnormal glucose tolerance is described in subjects with cystic fibrosis (CF) since childhood. OBJECTIVE The aims of the study were to compare oral glucose tolerance test (OGTT) and continuous glucose monitoring system (CGMS) in the diagnosis of altered glucose metabolism, and to longitudinally evaluate the role of CGMS in predicting glucose metabolism deterioration in children with CF. METHODS Seventeen children with CF and 14 controls were enrolled (mean age 13.3+/-3.0 years). All subjects underwent OGTT and CGMS registration. On the basis of OGTT, children were classified as normal glucose tolerance, impaired glucose tolerance (IGT), IGT plus at least one glucose value above 200 mg/dl at intermediate OGTT points (IGT+200) and CF-related diabetes (CFRD). HbA1c, glucose area under the curve, insulin sensitivity, and insulinogenic and disposition indexes were also considered. Subjects with CF underwent another OGTT after 2.5 years. RESULTS Baseline OGTT revealed 3/17 (7.6%) children with CF with at least one glucose value above 200 mg/dl (1 CFRD and 2 IGT+200), while CGMS revealed 6/17 (35.3%) children with glucose excursions above 200 mg/dl (P=0.010). None of the controls showed glucose over 200 mg/dl either at OGTT or at CGMS. At the 2.5-year follow-up OGTT, all the six subjects who had diabetic glucose excursion (i.e. >200 mg/dl) at baseline CGMS presented IGT+200 or CFRD. In logistic regression analysis, CGMS diabetic excursion was the strongest predictor of IGT+200 and CFRD (P<0.001). CONCLUSIONS CGMS could be a useful tool to predict glucose metabolism derangements in children affected by CF.

A multi-centre randomized trial of two different doses of nicotinamide in patients with recent-onset Type 1 diabetes (the IMDIAB VI)

Intensive insulin therapy is the gold standard by which Type 1 diabetes is treated. In addition to this therapy, administration of nicotinamide (NA) can be beneficial. This concept is reinforced by the results of a recent meta‐analysis of the use of NA in patients with recent‐onset Type 1 diabetes.

Menarche in type 1 diabetes is still delayed despite good metabolic control

OBJECTIVE To analyze the age at menarche of girls with type 1 diabetes (T1D) who were diagnosed with the disease before puberty and compare it with that of an age-matched group of normal girls. Previous studies on the appearance of menarche showed that the mean age of onset of menarche is delayed in girls affected by T1D compared with normal girls. DESIGN Case-control study. SETTING Patients and controls in an academic research environment. PATIENT(S) We studied, retrospectively, the charts of 162 consecutive girls with T1D born in a geographically defined region between 1984 and 1994 with a mean disease duration of 3-5 years, all of whom were on intensive insulin therapy since diagnosis of T1D. The control group consisted of 214 normal girls born between 1984 and 1994, who agreed to fill in an anonymous questionnaire regarding age at menarche and other clinical information. INTERVENTION(S) There was no intervention per se in the study. Age at menarche appears as a dependent variable of body mass index (BMI), HbA1c, and so on. MAIN OUTCOME MEASURE(S) BMI, HbA1c, and duration of T1D at menarche were considered among the potential factors affecting the age of menarche. RESULT(S) Age at menarche in girls with T1D was significantly delayed compared with control girls (12.6 +/- 1.5 years vs. 12.25 +/- 1.4 years, respectively). HbA1c levels and BMI did not influence the age at menarche. CONCLUSION(S) Despite intensive insulin therapy and good metabolic control since diagnosis of T1D, the age at menarche is still delayed in girls who develop T1D before puberty.

No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes.

Keywords Chronic.Durability.Efficacy.Glibenclamide.KCNJ11 gene.Kir6.2.Mutations.Permanent neonataldiabetes.Sulfonylurea.TherapyAbbreviationsDEND Developmental delay, epilepsy and neonataldiabetesiDEND Intermediate DENDTo the Editor: Patients with permanent neonatal- orinfancy-onset diabetes mellitus associated with activatingmutations of KCNJ11 and ABCC8 genes, which encodethe ATP-sensitive potassium channel of the pancreatic betacell, can be successfully weaned from insulin andtransferred to sulfonylureas [1, 2]. Individuals carryingspecific mutations of KCNJ11 or ABCC8 may present withdevelopmental delay, epilepsy and neonatal diabetes(DEND) syndrome or intermediate DEND (iDEND), i.e.may have, in additionto diabetes, motor/mental developmen-tal delay with or without epilepsy. Notably, patients withDEND may require higher doses of sulfonylureas to attainproper metabolic control [3]. Glibenclamide, a long-actingsulfonylurea largely used in the therapy of type 2 diabetes, isoften used to treat patients with neonatal- or infancy-onsetdiabetes due to KCNJ11 or ABCC8 mutations [1–4].

The Response to Gonadotropin Releasing Hormone (GnRH) Stimulation Test Does Not Predict the Progression to True Precocious Puberty in Girls With Onset of Premature Thelarche in the First Three Years of Life

CONTEXT Premature thelarche in early childhood may evolve into true precocious puberty. The individuation of cases progressing to precocious puberty is challenging. OBJECTIVE We analyzed the parameters predictive for progression in girls younger than 3 years. DESIGN AND SETTING We conducted a retrospective longitudinal study. PATIENTS AND METHODS A total of 450 girls referred for premature thelarche were initially evaluated, 353 were clinically monitored at 3-month intervals, and 97 underwent endocrine and imaging assessment. Central precocious puberty (CPP) was diagnosed in girls showing LH peak response to GnRH testing >5 mU/mL with tuber cinereum hamartoma at magnetic resonance imaging, or with normal magnetic resonance imaging but progression of puberty during follow-up. MAIN OUTCOME MEASURE We measured the progression to precocious puberty. RESULTS Idiopathic premature thelarche (IPT) was diagnosed in 85 of the 97 girls who underwent extensive evaluation, CPP in nine girls, and peripheral precocious puberty in three girls. The uterus was >34 mm in six (7%) IPT girls and six (66.6%) CPP girls. Basal LH was >0.2 mU/mL in one (1.17%) IPT girl and eight (88.8%) CPP girls. LH peak was >5 mU/mL in 31 (36.4%) IPT girls and nine (100%) CPP girls. LH peak/FSH peak ratio was >1 in six (66.6%) CPP girls. CONCLUSIONS None of the available tests alone allows identification of girls who will progress to precocious puberty. Elevated LH responses to GnRH are common but are not related to progression toward puberty. The combined measurement of basal LH and longitudinal diameter of the uterus represents a reliable screening approach to identify subjects who should undergo GnRH testing.

Early and progressive insulin resistance in young, non-obese cancer survivors treated with hematopoietic stem cell transplantation.

It is unclear whether there is a causative relationship between the development of metabolic syndrome (MS) and increased risk of early cardiovascular morbidity in patients receiving hematopoietic stem cell transplantation (HSCT) during childhood. Early identification of risk factors associated with insulin resistance, MS, and abnormal glucose tolerance during childhood or adolescence in these patients could represent a useful tool for preventing cardiovascular disorders.

Bone and body composition analyzed by Dual-energy X-ray Absorptiometry (DXA) in clinical and nutritional evaluation of young patients with Cystic Fibrosis: a cross-sectional study

Backgroundthe improved general therapy has led to reduced morbidity and mortality from Cystic Fibrosis (CF), and bone status may have a potentially greater clinical impact.We investigated the correlation between the severity of the clinical condition, bone status and body composition parameters, in a group of children and young adults with CF.Methodswe measured lumbar spine bone density and total body composition by dual energy x-ray absorptiometry (DXA) in 82 consecutive CF patients (42 males; median age: 13 years - range: 5-30). Eighty-two healthy subjects, matched for age, gender, height and pubertal stage were recruited as a control group.Results37 patients (45.1%) had a normal bone mineral density (BMD). A BMD reduction were observed in 45 (54.8%) patients. Lumbar spine Z score was positively related to Body Mass Index (BMI) and a higher Shwachman-Kulczycki score, and negatively related to Crispin-Norman score. A positive and significant correlation was also observed between lumbar spine Z score and total body composition.Conclusiona significant BMD reduction can be present early in CF children and adolescents. A careful follow up of bone status is required starting in childhood.